Trefoil Factors and Methods of Treating Proliferation Disorders Using Same

A method of inhibiting proliferation and/or survival of a tumor cell, comprising contacting said cell with a compound that inhibits the expression of a trefoil factor (TFF) gene, wherein said TFF gene is TFF1 or TFF2, said compound comprising one or more iRNAs or one or more DNA molecules encoding one or more iRNAs, wherein the expressed iRNAs interfere with the mRNA of the TFF1 or TFF2 genes and inhibit expression of said TFF1 or TFF2 genes, thereby inhibiting proliferation and/or survival of said cell.

A method of inhibiting proliferation and/or survival of a tumor cell, comprising contacting said cell with a compound that inhibits the expression of a trefoil factor 3 (TFF3) gene, said compound comprising one or more iRNAs comprising the nucleotide sequence selected from the group consisting of SEQ ID NO:

• 9-11 or one or more DNA molecules encoding one or more iRNAs comprising the nucleotide sequence selected from the group consisting of SEQ ID NO:
• 9-11, wherein the expressed iRNAs interfere with the mRNA of the TFF3 gene and inhibit expression of said TFF3 gene, thereby inhibiting proliferation and/or survival of said cell.

A method of inhibiting proliferation or survival of a tumor cell, comprising contacting said cell with a peptide antagonist of a TFF, wherein said antagonist is selected from the group consisting of (a) a function interfering mutant of a TFF of SEQ ID NO:25 comprising a non-identical amino acid at positions 23, 24, 25, 46, 47 or 57 and (b) a fragment of a TFF of SEQ ID NO:25, wherein said antagonist inhibits binding of an endogenous TFF to a TFF receptor in said cell or inhibits TFF dimerization, aggregation or functional activity.

A method of diagnosing a tamoxifen-resistance or a predisposition to developing said resistance, comprising detecting the level of TFF3 expression in a subject-derived tissue sample, wherein an increase in said level compared to a normal control level indicates that said subject comprises a tamoxifen-resistant tumor or is at risk of developing said tumor.

A method of treating or preventing cancer or a cell proliferation and/or survival disorder in a subject in need thereof, the method comprising regulating the expression of a trefoil factor (TFF) gene, wherein said TFF gene is TFF1 or TFF2, by administering a composition comprising one or more iRNAs or one or more DNA molecules encoding one or more iRNAs, wherein the expressed iRNAs interfere with the mRNA of the TFF1 or TFF2 gene and regulate expression of said TFF1 or TFF2 gene, thereby treating or preventing said cancer or cell proliferation and/or survival disorder.

A method of treating or preventing cancer or a cell proliferation and/or survival disorder in a subject in need thereof, the method comprising regulating the expression of a trefoil factor 3 (TFF3) gene by administering a composition comprising one or more iRNAs comprising the nucleotide sequence selected from the group consisting of SEQ ID NO:

• 9-11 or one or more DNA molecules encoding one or more iRNAs comprising the nucleotide sequence selected from the group consisting of SEQ ID NO:
• 9-11, wherein the expressed iRNAs interfere with the mRNA of the TFF3 gene and regulate expression of said TFF3 gene, thereby treating or preventing said cancer or cell proliferation and/or survival disorder.

A method of treating or preventing cancer or a cell proliferation and/or survival disorder in a subject in need thereof, the method comprising regulating the expression or activity of a trefoil factor (TFF) protein by administering a composition comprising one or more peptide antagonists or one or more DNA molecules encoding one or more peptide antagonists, wherein the expressed peptide antagonists interfere with the mRNA the expression or activity of the TFF protein, thereby treating or preventing said cancer or cell proliferation and/or survival disorder.

An isolated nucleic acid comprising the nucleotide sequence selected from the group consisting of SEQ ID NO:

• 3-11.

A pharmaceutical composition comprising an isolated nucleic acid comprising the nucleotide sequence selected from the group consisting of SEQ ID NO:

• 3-11.

An isolated nucleic acid comprising the nucleotide sequence selected from the group consisting of SEQ ID NO. 1 and 2.

A pharmaceutical composition comprising an isolated nucleic acid comprising the nucleotide sequence selected from the group consisting of SEQ ID NO. 1 and 2.

An isolated nucleic acid comprising the nucleotide sequence selected from the group consisting of SEQ ID NO. 5 and 6.

A pharmaceutical composition comprising an isolated nucleic acid comprising the nucleotide sequence selected from the group consisting of SEQ ID NO. 5 and 6.

A method of increasing sensitivity of a drug-resistant tumor to a chemotherapeutic agent, comprising contacting said drug-resistant tumor with an antibody composition that binds to a TFF gene product.

A peptide antagonist of TFF comprising a TFF mutant, said mutant comprising a non-identical amino acid at position 20, 21, 42, 43, or 58 of SEQ ID NO:36 (TFF1).

A peptide antagonist of TFF comprising a TFF mutant, said mutant comprising a non-identical amino acid at position 21, 22, 43, or 44 of SEQ ID NO:37 (TFF2).

A peptide antagonist of TFF comprising a TFF mutant, said mutant comprising a non-identical amino acid at position 70 71, 92, 93, or 103 of SEQ ID NO:37 (TFF2).

A peptide antagonist of TFF, comprising a fragment of TFF1, 2, or 3, said fragment being linked to a heterologous polypeptide.